Changes in epitopes for thyroid-stimulating antibodies in Graves' disease sera during treatment of hyperthyroidism: therapeutic implications.

To determine whether there are changes in epitope recognition by stimulating TSH receptor antibodies (TSHRAbs) during treatment of hyperthyroidism and to evaluate the clinical relevance of such changes, we serially measured the activity of IgG preparations from 39 patients with Graves' disease over an 8-month period. To measure epitope changes of the stimulating TSHRAbs, we used Chinese hamster ovary (CHO) cells transfected with wild-type human TSHR (hTSHR) or TSHR chimeras with residues 90-165 (Mc2) substituted by equivalent residues of the rat LH/CG receptor. When initially examined, 37 of the 39 patients had significant stimulating TSHRAb activity measured with wild-type CHO-hTSHR cells. Serial measurements of stimulating TSHRAb activity in Mc2 chimera-transfected cells divided the 39 patients into three distinct groups. Thus, 10 patients (heterogeneous epitope group) exhibited low but significant activity in Mc2 chimera assays at the start of the study; 10 patients who were initially negative in Mc2 chimera assays remained negative (persistently homogeneous epitope group); and 19 patients who were initially negative in Mc2 chimera assays became transiently or persistently positive during treatment, despite a simultaneous decrease in TSHRAb activity measured with wild-type TSHR (changing epitope group). The functional stimulating TSHRAb epitope thus changed from residues 90-165 to residues outside this region in the last group, which comprises nearly two-thirds of the initially Mc2-negative patients (19 of 29) and one-half of all patients (19 of 39). Patients in the changing epitope group responded more quickly and to lower doses of methimazole than patients in the persistently homogeneous epitope group, behaving in this respect exactly as the patients in the heterogeneous epitope group. Additionally, although the decrease in stimulating TSHRAb activities during the 8-month treatment period was similar in the two groups, the thyrotropin binding inhibitor immunoglobulin (TBII) activities decreased more rapidly in patients in the persistently homogeneous epitope group than in patients in the changing epitope group (P < 0.05). There were no differences in initial stimulating TSHRAb or TBII activities, degree of hyperthyroidism, goiter size, or prior duration of symptoms between the persistently homogeneous epitope group and changing epitope group. In summation, we show that the epitopes of stimulating TSHRAbs in Graves' disease patients may change during their clinical course or treatment period, and that the change is from antibodies recognizing N-terminal TSHR residues 90-165 to antibodies recognizing other regions of the TSHR. We also show that the development of stimulating TSHRAbs with this heterogeneous epitope or their presence at the initial screening for disease activity seems to be associated with increased responsiveness to antithyroid drug therapy. We suggest, therefore, that Mc2 chimera assays may be useful to predict the response of patients to antithyroid drug therapy.